Large-Scale Application of High-Throughput Molecular Mechanics with Poisson−Boltzmann Surface Area for Routine Physics-Based Scoring of Protein−Ligand Complexes

We apply a high-throughput formulation of the molecular mechanics with Poisson−Boltzmann surface area (htMM-PBSA) to estimate relative binding potencies on a set of 308 small-molecule ligands in complex with the proteins urokinase, PTP-1B, and Chk-1. We observe statistically significant correlation to experimentally measured potencies and report correlation coefficients for the three proteins in the range 0.72−0.83. The htMM-PBSA calculations illustrate the feasibility of procedural automation of physics-based scoring calculations to produce rank-ordered binding-potency estimates for protein−ligand complexes, with sufficient throughput for realization of practical implementation into scientist workflows in an industrial drug discovery research setting.